Abstract C040: Association between rs16906115 and other germline variants associated with immunotherapy modulation and breast cancer risk across populations

Abstract Introduction: Germline (inherited) genetic variants in immunoregulatory genes have been recently characterized in the context of immunotherapy response and outcomes, such as developing immune checkpoint inhibitor-associated immune-related adverse events. Innate immune features are increasingly thought to contribute to the trajectory of breast cancers, particularly the triple-negative subtype. The impact of immunoregulatory variants, particularly those associated with prediction or prognostication in cancer, has not been well characterized in the context of cancer risk. We hypothesize that germline immunoregulatory variants associated with prediction or prognostication in cancer are associated with increased breast cancer risk and differential breast cancer risk across subpopulations. Methods: We used the All of Us (AoU) Research Program Controlled Tier database to design a case-control study to assess the effects of germline immunoregulatory variants reported in the literature as predictive or prognostic (rs16906115, rs56328422, rs3026321, rs1131769, rs30187 or rs10954213). Cases were participants reported as having a breast cancer diagnosis, and controls were participants excluded from this group. We matched cases and controls in a 1:5 ratio by age, self-reported race, and geographic region. We assessed both crude and self-reported racial group odds ratios. Results: Our study included 10803 cases and 54015 controls. The median age group was 60+. Participants represent 443 distinct zip code areas. In this study, 71.31% participants reported as White, 13.09% participants as Black/African American, 11.18% participants as Hispanic, 2.28% participants self-identified as from more than one population, 1.95% participants as Asian, and less than 1% Middle Eastern/North African or Native Hawaiian/Pacific Islander. The geographic matching limitation restricted inclusion of Native participants. We found that all variants studied were significantly associated with breast cancer risk, with pooled Mantel-Haenszel odds ratios as follows: rs16906115 = 1.20 (1.13-1.26); rs56328422 = 1.22 (1.16-1.28); rs3026321= 1.19 (1.12-1.26); rs1131769 = 1.83 (1.73-1.93); rs30187 = 1.54 (1.47-1.61); rs10954213 = 1.46 (1.40-1.53). The Breslow-Day test was also significant for all variants when stratifying by self-reported race (even among groups > 1%), suggesting that cancer risk increases associated with these immunoregulatory variants are mediated in part through these groups. Discussion: Germline immunoregulatory variants are associated with risk of breast cancer, with self-reported race as a potential mediator. This matched case-control study leverages AoU to study the potential role of inherited immune modulators in contributing to cancer risk, both overall and across populations. Further analyses will leverage genomic ancestry to refine this result as well as account for other known modifiers of the relationship between the immune system and cancer risk. Citation Format: Jonathan Wooten, Clayton Yates, Padma S. Rajagopal. Association between rs16906115 and other germline variants associated with immunotherapy modulation and breast cancer risk across populations [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C040.